Direct titanium-mediated conversion of ketones into enamides with ammonia and acetic anhydride

Article abstract of DOI:10.1002/anie.201107601

A one-step conversion of ketones into N-acetyl enamides was developed. The process employs safe and inexpensive reagents, proceeds under mild conditions, and tolerates diverse functional groups. The addition of edte (N,N,N ,N -tetrakis(2-hydroxyethyl)ethy

Full text of DOI:10.1002/anie.201107601

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DOI: 10.1002/anie.201107601
Enamide Synthesis
Direct Titanium-Mediated Conversion of Ketones into Enamides with
Ammonia and Acetic Anhydride
Jonathan T. Reeves,* Zhulin Tan, Zhengxu S. Han, Guisheng Li, Yongda Zhang, Yibo Xu,
Diana C. Reeves, Nina C. Gonnella, Shengli Ma, Heewon Lee, Bruce Z. Lu, and
Chris H. Senanayake
N-Acyl enamides are useful compounds in organic synthesis.
In the realm of catalytic asymmetric hydrogenation, they are
among the most exhaustively studied class of substrates, and
provide access to valuable chiral amine building blocks.[1]
These substrates have also demonstrated broad utility in
This reaction was first described in 1975 by Barton and co-
workers. After a first step of oxime formation, the ketoxime
was then treated with Ac2O and either pyridine at reflux,
Cr(OAc)2, or Ti(OAc)3 for reductive acylation.[13] Subse-
quently, numerous alternative reducing agents were devel-
oped.[14] The most commonly employed reductant is Fe
powder, which was first demonstrated by Barton and Zard
in 1985[14a] and subsequently developed by Burk and Zhang in
1998.[14b,c] From a large scale perspective, the use of high-
energy hydroxylamine, generating a high-energy oxime
intermediate, and reducing the oxime at high temperatures
present safety concerns. In addition, the workup of the Fe
process is often tedious, requiring filtration of large amounts
of inorganic salts. While several alternatives to Fe metal have
emerged recently, these still rely on the same overall two-step
process through a ketoxime.[14d–g] Our own requirements for
large-scale synthesis of N-acetyl enamides for asymmetric
hydrogenation prompted us to develop a more direct and
process-friendly alternative in which hydroxylamine is
replaced with ammonia. Herein we describe a direct, redox-
free synthesis of enamides from ketones, ammonia, and Ac2O
mediated by Ti(OiPr)4. In addition, we introduce the use of
edte (N,N,N’,N’-tetrakis(2-hydroxyethyl)ethylenediamine) to
effect water solubilization of the Ti and allow a simple
extractive workup.
À
catalytic asymmetric C C bond forming processes such as
aza–ene,[2] Michael,[3] Friedel–Crafts,[4] cycloaddition,[5] and
arylation[6] reactions. Despite the extensive applications of N-
acyl enamides, their preparation remains challenging. The
direct condensation of acetamide with ketones, while attrac-
tive in its simplicity, proceeds either in low yields or not at all
for the majority of ketone substrates.[7] The Pd-catalyzed
cross-coupling of vinyl electrophiles with amides[8] and the
Heck reaction of N-vinylacetamide with aryl halides[9] often
require additional steps for preparation of coupling precur-
sors and employ a costly transition metal catalyst.[10] The
addition of alkyl magnesium or alkyl lithium reagents to
nitriles followed by trapping with Ac2O or AcCl has limited
functional-group tolerance[11] and requires low reaction
temperatures.[12] By far the most commonly employed proce-
dure is the two-step conversion of ketones through ketoximes
(Scheme 1).[13]
Our strategy for enamide synthesis was based on con-
densation of a ketone with ammonia to give an N-unsub-
stituted imine or enamine, followed by N-acetylation on
addition of Ac2O. The imine formation presented a challenge
due to the volatility of ammonia, which excluded the common
method for imine formation by azeotropic distillation for
removal of water.[15] Therefore the condensation with NH3 at
room temperature in the presence of various dehydrating
agents was explored. Acetophenone 1 was treated with a
dehydrating agent (2 equiv) and an ammonia source at room
temperature for 24 h, followed by quenching with Et3N and
Ac2O (Table 1). Little or no enamide 2 was observed with
conventional desiccants and ammonia (entries 1–4). The use
of sodium tetraborate (Na2B4O7) or boric anhydride (B2O3) in
THF or NMP gave modest conversion to product (entries 5–
7). This prompted screening of other boron reagents, and the
discovery that certain trialkyl borates, in combination with
NH4Br/Et3N as the ammonia source, gave moderate con-
versions to product. The most effective boron reagent was 2-
isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
Scheme 1. Conventional two-step enamide synthesis and the direct Ti-
mediated method.
[*] Dr. J. T. Reeves, Z. Tan, Dr. Z. S. Han, Dr. G. Li, Dr. Y. Zhang, Y. Xu,
Dr. D. C. Reeves, Dr. S. Ma, Dr. H. Lee, Dr. B. Z. Lu,
Dr. C. H. Senanayake
Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc.
Ridgefield, CT 06877 (USA)
E-mail: jonathan.reeves@boehringer-ingelheim.com
Dr. N. C. Gonnella
Analytical Development, Boehringer Ingelheim Pharmaceuticals, Inc.
Ridgefield, CT 06877 (USA)
(entry 11), which gave a 59% conversion to 2. The best results
were obtained by using titanium alkoxides, however, with
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201107601.
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Table 1: Screening results for direct enamide formation with NH3.[a]
Entry
Dehydrant
NH3 source
Solvent[b]
Conversion
[%][c]
Scheme 2. Structure of edte and its complex with titanium.
1
2
3
4
5
6
7
8
MgSO4
CaH2
ZnBr2
NH3/MeOH
NH3/MeOH
NH3/MeOH
NH3/MeOH
NH3/MeOH
NH3/MeOH
NH3/MeOH
NH4Br/Et3N
NH4Br/Et3N
NH4Br/Et3N
NH4Br/Et3N
NH4Br/Et3N
NH3/MeOH
NH3/MeOH
NH4Br/Et3N
NH3/MeOH
THF
THF
THF
THF
THF
NMP
NMP
THF
THF
THF
THF
THF
PhMe
PhMe
THF
PhMe
0
8
0
5
hydroxypropyl)ethylenediamine (edtp) was equally effective,
but more difficult to dispense than edte due to its greater
viscosity. Importantly, both edte and edtp are inexpensive and
commercially available in ton quantities.
LiCl
Na2B4O7
Na2B4O7
B2O3
27
40
38
<5
34[d]
<5
59[d]
32
85
96[e]
67
22
B(OMe)3
B(OiPr)3
B(OtBu)3
pinBOiPr[f]
Al(OiPr)3
Ti(OEt)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OtBu)4
Thus, after completion of the reaction, 2.1 equiv of edte
(1.05 equiv relative to Ti(OiPr)4) was charged, the reaction
mixture heated at 558C for 15 min (to effect complete
complexation of Ti with edte),[19] and after cooling to room
temperature, the reaction mixture was diluted with aqueous
NH4OH and EtOAc.[20] This resulted in two clear phases, and
allowed a normal extractive workup (Scheme 3). The use of
edte should be applicable to the workup of other reactions
employing stoichiometric titanium alkoxides, such as sulfin-
imine formation and reductive amination.[16]
9
10
11
12
13
14
15
16
[a] Typical reaction conditions: 2 equiv dehydrating agent, 2 equiv NH3
source, 3 volumes of solvent, RT, 24 h, then 4 equiv Et3N, 2 equiv Ac2O.
[b] THF=tetrahydrofuran, NMP=N-methylpyrrolidinone. [c] HPLC
conversion of 1 to 2. [d] After 48 h. [e] Yield of isolated product: 81%.
[f] 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Ti(OiPr)4 being most effective (entry 14).[16] The use of
ammonia in MeOH (1.5 equiv of 7n solution) as the ammonia
source and toluene as solvent was found to be optimal, and an
81% yield of isolated enamide 2 was obtained under these
conditions after workup and chromatography. The use of
ammonium salts in combination with Et3N or other bases in
place of 7n NH3 in MeOH led to lower reaction rates and
lower yields.
Scheme 3. Addition of edte to the reaction mixture enables simple
extractive workup.
While optimal reaction conditions which employed cheap,
safe, and widely available reagents had been identified, the
workup of the reaction required further optimization. Tradi-
tionally, reactions employing titanium alkoxides in combina-
tion with products which are not stable to aqueous acid are
worked up by pouring the reaction mixture into brine or
aqueous base.[16] This results in the precipitation of insoluble
TiO2 which is subsequently filtered, and the biphasic filtrate is
worked up extractively. The filtration of TiO2 is extremely
slow, however, even on relatively small scales. This difficulty
has been noted by others, and has unfortunately been the
cause of abandonment of many Ti-based procedures for large
scale applications.[17] When first scaling up the present
reaction, the filtration required an unacceptable time (several
hours to days) to complete, thus rendering the process
impractical for large scale. Numerous variations of the
aqueous solution used for quenching, order of addition, and
filtration medium led to no improvement in filtration rate. We
then investigated whether the Ti could be converted into a
water-soluble species to avoid the filtration of TiO2 altogether
and allow an extractive workup. After screening several
reagents, we found that edte effectively converted the Ti-
(OiPr)4 into a water-soluble and water stable complex
(Scheme 2).[18] The related reagent N,N,N’,N’-tetrakis(2-
The scope of the enamide synthesis with acyclic ketones
was explored (Table 2).[21] A variety of aryl methyl ketones
were converted to the corresponding enamides in good yields.
The reaction was tolerant of many functional groups, includ-
ing halides, nitro groups, amides, esters, nitriles, and thio-
ethers. The reaction with cyclohexyl methyl ketone (entry 16)
and the related 4-piperidinyl methyl ketone (entry 21)
proceeded to give exclusively the less substituted enamide,
which may be difficult to achieve by alternative methods. The
reaction was tolerant of a-branched ketones (entries 17, 18).
Importantly, though the propiophenone substrate in entry 17
gave a mixture of E/Z isomers, it has been demonstrated that
such mixtures are hydrogenated in high enantioselectivity.[1]
In addition to aryl alkyl ketones, the reaction occurred
equally well with heterocyclic ketones (entries 19–23). An
enone provided a dienamide in good yield (entry 24).
Benzylacetone reacted to give only the terminal enamide,
but a significant amount of the methoxy aminal 28 was also
formed in this case (entry 26). Phenylacetone gave exclusively
the internal enamide with good selectivity favoring the Z-
isomer (65% yield, Z:E = 5.5:1, entry 27). This result com-
pares favorably with that obtained by the condensation of
acetamide (24% yield, Z:E = 1.8:1).[7a] An aldehyde was
converted in low yield to the corresponding enamide
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Table 2: Scope of enamide formation with acyclic ketones.[a]
(entry 28). The enamide formation was also amenable to
cyclic ketone substrates (Table 3). Indanone, tetralone, chro-
manone, and suberone substrates all provided the corre-
sponding enamides in good yields.
Entry
1
Enamide (yield)[b]
Entry
15
Enamide (yield)[b]
Table 3: Scope of enamide formation with cyclic ketones.[a]
Entry
1
Enamide (yield)[b]
Entry
3
Enamide (yield)[b]
2
3
16
17
2
4
4
5
6
18
19
20
[a] Reaction conditions: 10 mmol ketone, 15 mmol NH3/MeOH,
20 mmol Ti(OiPr)4, 6 mL PhMe, RT, 24 h; 40 mmol Et3N, 20 mmol Ac2O,
RT, 1–3 h. [b] Yield of isolated products.
The intermediate formed from the reaction of ketones
with amines in the presence of Ti(OiPr)4 has been postulated
as an O-titanium hemiaminal by several groups, although no
direct spectroscopic evidence has been provided.[16a,c,22] On
the other hand, in the context of their work on reductive
amination, Brunel and co-workers studied the species formed
7
8
9
21
22
23
1
from acetophenone, benzylamine and Ti(OiPr)4 by H and
13C NMR spectroscopy and reported no evidence of an O-
titanium hemiaminal but suggested the intermediacy of
acetophenone N-benzyl imine.[23] In order to gain insight
into the intermediate generated in the present reaction, we
performed IR and NMR experiments (Scheme 4). Thus,
acetophenone 1 was treated with methanolic ammonia and
Ti(OiPr)4 in C6D6, and the reaction solution was allowed to
stir for 20 h at room temperature. IR analysis of the reaction
showed the disappearance of the acetophenone carbonyl at
10
11
12
24
25
26
1692 cmÀ1 concurrent with the appearance of a new peak at
1626 cm , a frequency typical of an aryl ketimine C N
À1
=
bond.[24] Analysis of the 13C NMR spectrum showed the
disappearance of the acetophenone carbonyl signal at
197 ppm and the appearance of a new peak at 175 ppm, also
a frequency consistent with a ketimine species.[24] The 13C
HMBC spectrum showed strong correlations between the
carbon signal at 175 ppm and the two ortho protons at
7.51 ppm as well as the methyl protons of the acetophenone
moiety at 2.07 ppm. These correlations confirmed the identity
13
14
27
28
of the 175 ppm signal as the former carbonyl carbon. The 15
N
[a] Reaction conditions: 10 mmol ketone, 15 mmol NH3/MeOH,
20 mmol Ti(OiPr)4, 6 mL PhMe, RT, 24 h; 40 mmol Et3N, 20 mmol Ac2O,
RT, 1–3 h. [b] Yield of isolated products. [c] 2:1 mixture of Z:E isomers.
[d] 5.5:1 mixture of Z:E isomers.
Scheme 4. Spectral data for proposed imine intermediate 35.
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HMBC spectrum showed a strong correlation between the
methyl protons at 2.07 ppm and a nitrogen signal at 89 ppm.
The 15N HMBC data, together with the 13C HMBC data,
suggest the formation of an imine species. Furthermore, the
15N HSQC spectrum showed no evidence of an N-H
correlation with the nitrogen resonance at 89 ppm. In
addition the 1H NOESY spectrum revealed correlations
between the aromatic protons at 7.15 and 7.51 ppm and the
methyl protons on the titanium isopropoxide moiety at
1.09 ppm establishing a proximity of < 5 ꢀ. Based on these
spectral data, we postulate that the imine nitrogen is
covalently bound to titanium as shown by 35 in Scheme 4.[25]
The nature of the titanium center is more difficult to specify,
as methanol may be exchanging with the isopropoxy ligands
on the metal, and the imine-titanium complex may be di-
nuclear.[26]
Scheme 6. Proposed mechanism of enamide formation.
group tolerance. This process avoids the safety concerns of the
hitherto commonly employed two-step ketoxime reductive
acylation process, namely the use of high-energy hydroxyl-
amine and oxime intermediates. The process requires no
reduction, and therefore avoids the need for large quantities
of Fe powder and the associated post-reaction filtration of Fe
salts. Spectroscopic analysis of the reaction mixture con-
firmed the formation of an imine and not a hemiaminal
intermediate prior to acetylation. To overcome the difficult
filtration of TiO2 encountered in a traditional aqueous
quench, the use of edte to generate a water-soluble and
water-stable titanium complex was employed. This enables a
simple extractive workup amenable to large scale synthesis.
The use of edte in the workup of reactions using titanium
alkoxides should be of general utility to both academic and
industrial chemists.
In order to further corroborate structure 35, we attempted
to prepare it from an alternate route (Scheme 5). Thus,
acetophenone imine was synthesized by the addition of MeLi
to benzonitrile 36 and quenching with MeOH, followed by
Received: October 28, 2011
Revised: December 7, 2011
Published online: January 3, 2012
Scheme 5. Independent generation of 35 from acetophenone imine 37.
filtration and concentration.[15b] Imine 37 was cleanly formed
as a 2.1:1 mixture of NH isomers. Treatment of a C6D6
solution of 37 with 2 equiv of Ti(OiPr)4 and aging for 18 h
gave a species which by 1H and 13C NMR contained very
broad signals, suggesting the formation of a paramagnetic
complex. On addition of MeOH (a volume equal to that
present in the reaction from the 7n NH3/MeOH solution) and
aging for 30 min, the 1H and 13C NMR spectra showed
Keywords: ammonia · enamides · synthetic methods · titanium
.
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enamide 2.[27]
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economical one-step synthesis of enamides from ketones
using Ti(OiPr)4, ammonia, and acetic anhydride. The reaction
occurs under mild conditions and shows excellent functional-
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[19] We found that stirring the reaction mixture after edte addition at
room temperature required several hours to effect complete
complexation of all titanium alkoxides with edte.
[20] Pure water may also be used, though small amounts of hydrolysis
of the enamide back to the ketone occurred due to the lower pH
of the solution. Using NH4OH minimizes enamide hydrolysis
during the workup. The use of alkaline bases (NaOH, Na2CO3,
KOH) was not effective and resulted in TiO2 formation.
[21] The use of trifluoroacetic anhydride in place of Ac2O was not
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